This study is designed to test a novel paradigm that the human genome dynamically interacts with the environment and that epigenetic mechanisms are at the interface of genome- environment interactions. The human genome is marked by structural variations including large copy number variations and differences in repetitive sequences. Environmental pollutants such as polychlorinated biphenyls (PCBs) are associated with DNA methylation changes. Chromosome 15q11-q13 duplication syndrome (Dup15q), is one of the most common copy number variations (CNV) observed in neurodevelopmental disorders. This proposal is based on the findings that human brain samples with Dup15q syndrome showed significantly higher levels of the persistent organic pollutant PCB 95 than controls or idiopathic autism cases, and that the interaction of both Dup15q and PCB 95 cumulatively impacted the methylation of over 1000 genes, enriched for autism candidate genes with synaptic functions. Three aims are proposed to test the overarching hypothesis that the cumulative impact of multiple risk factors converge on common gene pathways and are detectable as epigenetic signatures in early life tissues. The first aim seeks to determine the mechanism by which UBE3A overexpression interacts with PCB-95 exposure on histone H2A.Z biding sites genome-wide using next generation sequencing, siRNA knockdown, and CRISPR/Cas9 technologies. The second aim investigates the interaction between a human-relevant mixture of PCB congeners and UBE3A overexpression on the methylome and transcriptome in dental pulp stem cells derived from baby teeth from Dup15q and control children. The third aim seeks to identify potential methylation biomarkers of POP exposures and CNV in placenta samples from a human prospective autism study and a rhesus macaque model of maternal obesity. The results of these studies are expected to formally test the hypothesis that DNA methylation levels reduced by cumulative impacts of environmental pollutants and genetic changes may result in alterations in chromatin, leading to transcriptional changes and adverse health outcomes. In addition, epigenetic alterations of autism candidate genes involved in synaptogenesis are expected to be uncovered by this approach and be established as perinatal epigenetic biomarkers of cumulative risk assessments, as well as guiding future behavioral and pharmacological treatments. Finally, the results of these studies are expected to be broadly relevant to understanding the relationship between the genome, environmental exposures, and the epigenome in human health and disease.